Cel
Hematopoietic Stem Cells (HSCs) are at the origin of all blood cells needed throughout life. HSC transplantation is used to treat patients with blood related disorders. However, the number of HSCs available for clinic and research remains limited. The production of large quantities of HSCs in vitro, for example by reprogramming or transdifferentiation of somatic cells to a HSC stage, would be a good solution, but this remains extremely difficult. To overcome these problems, we must understand all the molecular and cellular events underlying the in vivo HSC formation. Because all adult HSCs are initially produced during embryonic development, it is clear that studying how HSCs are generated during ontogeny is of importance. We and others have demonstrated that specialized endothelial cells endowed with a hemogenic potential produce all HSCs. However, the exact anatomical site(s) of mammalian HSC origin and all steps leading to HSC production are unclear and highly controversial. In this ERC Starting Grant proposal, I describe comprehensive lines of experimentation to answer these fundamental questions. I first propose to develop a totally novel in vivo embryo rescue assay to unambiguously determine the exact site(s) of HSC origin. In this assay, candidate precursors will be tested for HSC potential by a novel in utero transplantation technique performed directly into developing HSC-deficient embryos. We will also determine how hemogenic endothelial cells generate HSCs (directly or via an intermediate population). Gene expression profiles and comparative analyses of these populations will be performed by RNA-Sequencing to determine the dynamic changes in gene expression and to identify key players in the HSC commitment process. I anticipate that our studies will significantly advance our understanding of normal HSC generation, and help to produce HSCs in vitro. Furthermore, it should also lead to a better comprehension of HSC dysfunction in diseases.
Dziedzina nauki
Zaproszenie do składania wniosków
ERC-2012-StG_20111109
Zobacz inne projekty w ramach tego zaproszenia
System finansowania
ERC-SG - ERC Starting GrantInstytucja przyjmująca
1011 JV AMSTERDAM
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